Chronic obstructive pulmonary disease (COPD) is a major global health burden and the associated morbidity and mortality are expected to expand in the next decades. Despite decades of research, no effective therapies exist to circumvent the irreversible alterations in lung structure and lung function decline. This failure reflects the complexity of COPD pathogenesis and our lack of understanding of the molecular and cellular responses to chronic cigarette smoke (CS) exposure. Further complicating our understanding of COPD is the fact that frequent viral infections challenge the immune system which magnifies pulmonary injury and remodeling in COPD. Our work has uncovered a role for natural killer (NK) cells, and the NKG2D activating receptor, as pivotal determinants of both the direct effects of CS exposure and the subsequent innate response to influenza that exacerbates disease progression in COPD. The present application examines mechanisms whereby chronic airway injury enhances NK cell-mediated inflammation and tissue destruction and the mechanisms whereby NK cell stimulation renders NK cells hyperresponsive to influenza infection. Given the important roles of NK cells in inflammation and the removal of infected or stressed cells, it is important to define the mechanisms that control NK cell function in COPD and define the mechanisms by which NK cells regulate the immune response to viral exacerbations in COPD. In this proposal, we hypothesize that chronic NK cell stimulation through the NKG2D receptor leads to a hyperresponsive NK cell phenotype which mediates both CS-induced pathologies and enhanced pathologies during viral exacerbations. We will explore the function of NK cells and the mechanistic role NKG2D activating receptor in viral exacerbations of COPD. Specifically, we will 1) Define the role of nucleic acid sensing toll-like receptors in regulating NK cell function n response to CS exposure, 2) Define NK cell effector functions and the role of NKG2D during viral exacerbations of COPD, and 3) Define NK cell function and NKG2D activity in COPD patients. We expect our research will identify key mechanisms involved in NK cell-mediated pulmonary pathology and allow us to identify therapeutic targets for CS- induced lung inflammation, injury and alveolar remodeling. Use of animal models allows us conduct mechanistic work in a model that replicates the principal pathologies and immune alterations reported in COPD patients and will have an impact on the interpretation of findings obtained in COPD patients by identifying molecular targets for intervention.